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0090-9556/04/3205-536-544$20.00
DMD 32:536-544, 2004

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COMPARATIVE HEPATIC AND EXTRAHEPATIC ENANTIOSELECTIVE SULFOXIDATION OF ALBENDAZOLE AND FENBENDAZOLE IN SHEEP AND CATTLE

G. Virkel, A. Lifschitz, J. Sallovitz, A. Pis, and C. Lanusse

Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Tandil, Argentina

The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle. The microsomal fractions were incubated with a 40 µM concentration of either ABZ or FBZ. Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 µM methimazole (MTZ) either with or without heat pretreatment (2 min at 50°C). ABZ and FBZ were metabolized to the (+) and (-) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ. The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (+) ABZSO production in both species. Liver sulfoxidation of FBZ by FMO was also enantioselective toward (+) OFZ (sheep = 65%; cattle = 79%). Cytochrome P450 was found to be mainly involved in the production of (-) ABZSO in the liver. MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue. A significant (p < 0.05) inhibition of (-) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle = 21%) and ketoconazole (sheep = 36%). Both CYP3A substrates induced a reduction in the production of (-) ABZSO (sheep = 67–78%, cattle = 50–78%) by lung microsomes. Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.

Address correspondence to: Dr. Guillermo L. Virkel, Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, UNCPBA, Campus Universitario, (7000) Tandil, Argentina. E-mail: gvirkel{at}vet.unicen.edu.ar




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